Substituted 2h-pyrano[2,3-c]pyridines, combinatory and focused libraries

FIELD: organic chemistry, pharmacy, biochemistry.

SUBSTANCE: invention relates to new substituted 2H-pyrano[2,3-c] of the general formula (1) eliciting ability to inhibit activity of protein kinase. In the general formula (1) X represents oxygen atom or group NR3; R1 represents group -C(O)R4, optionally substituted and optionally condensed azaheterocycle; R2 represents optionally substituted hydroxyl group or optionally substituted amino-group; R3 represents hydrogen atom or inert substitute meaning optionally substituted low- or non-reactive radical including such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, (C2-C12)-alkoxyalkyl, (C2-C10)-alkylsulfinyl, (C2-C10)-alkylsulfonyl, -(CH2)-O-(C1-C7-alkyl), -(CH2)m-N(C1-C7-alkyl)n, aryloxyalkyl, heterocyclyl wherein m and n have value from 1 to 7; R4 represents optionally substituted amino-group or hydrogenated optionally substituted azaheterocycle. Also, invention relates to combinatory and focused libraries consisting of compounds of the present invention and designated for the search of compound-hits and compound-leaders prepared by screening of these libraries for using in preparing medicinal agents.

EFFECT: valuable medicinal properties of compounds.

8 cl, 2 tbl, 6 ex

 

This invention relates to the search for new chemical substances and new physiologically active substances, compounds leaders and candidates in medicine (drug-candidates)that can be derived from the screening of combinatorial libraries, as well as to new combinatorial libraries.

More specifically, the present invention relates to new substituted 2H-pyrano[2,3-C]pyridinium and combinatorial library consisting of new 2H-pyrano[2,3-C]pyridines.

Substituted 2H-pyrano[2,3-C]pyridine have high potential physiological activity. So, for example, substituted 2H-pyrano[2,3-C]pyridine are cardiotonic agents [Merck Patent, EP 0308792, 19890329], have antigipertenzivnoe [G.Burrell, F.Cassidy, J.Evans, D.Lightowler, G.Stemp. J.Med. Chem. 1990, 33, 3023-3027] and antimicrobial [G.Wachter, M.Davis, A.Martin, S.Franzblau. J.Med. Chem. 1998, 41, 2436-2438] activity.

Given the high potential physiological activity 2H-pyrano[2,3-C]pyridines, it is important to develop new classes of heterocyclic compounds of this type and combinatorial libraries 2H-pyrano[2,3-C]-pyridines to search for biologically active compounds leaders.

To search for new biologically active compounds leaders inventors synthesized previously unknown 2H-pyrano[2,3-C]pyridine and developed a new combinatorial library comprising these compounds.

There is only a limited number zameshannyh 5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-ones, they are presented below in table 1.

Table 1.

Known 3-substituted 5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-ones.
No.FormulaNameLiterature
15-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-heKorytnyk, W.; Ahrens, H.; Angelino, N.; Kartha, G. J.Org. Chem. 1973, 38 (21), 3793-3797
23-amino-5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-heW. Korytnyk, H. Ahrens, J. Heterocycl. Chem. 1970, 7, 1013-1017
33-acetylamino-5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-heW. Korytnyk, H. Ahrens, J. Heterocycl. Chem. 1970, 7, 1013-1017
45-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carboxylic acidBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles, 1997, 45, 1715-1722; Dejardin, J., Bull. Soc. Chim. France, 1979, 289-298
5Ethyl ester of 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carboxylic acidBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles, 1997, 45, 1715-1722; Dejardin ., Bull. Soc. Chim. France, 1979, 289-298
65-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carbonitrileBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721
75-hydroxymethyl-8-methyl-3-phenyl-2H-pyrano[2,3-C]pyridine-2-heBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721
85-hydroxymethyl-8-methyl-3-(4-nitrophenyl)-2H-pyrano[2,3-C]pyridine-2-heBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721
95-hydroxymethyl-8-methyl-3-(pyridin-2-yl)-2H-pyrano[2,3-C]pyridine-2-heBrufla, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721
105-hydroxymethyl-8-methyl-3-(pyridin-4-yl)-2H-pyrano[2,3-C]pyridine-2-heMoffett, R.B. J Org. Chem., 1970, 35, 3596-3600
115-hydroxymethyl-8-methyl-3-(thiophene-2-yl)-2H-pyrano[2,3-C]pyridine-2-heBrufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721
123-(benzothiazol-2-yl)-5-hydroxy shall ethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-he Brufola, G.; Fringuelli, F.; Piermatti, O.; Pizzo, F. Heterocycles 1997, 45 (9), 1715-1721

The present invention relates to new substituted 8-methyl-2H-pyrano[2,3-C]pyridinium to combinatorial library and a focused library of new 8-methyl-2H-pyrano[2,3-C]pyridines.

Below are definitions of terms used in the description:

"Focused library" means a combinatorial library, or a combination of several combinatorial library, or a set of libraries and substances, specially organized for the purpose of increasing the probability of finding hits and leaders, or to improve the efficiency of their optimization. The design of focused libraries, typically associated with directional search effectors (inhibitors, activators, agonists, antagonists, etc.) certain biological targets (enzymes, receptors, ion channels, and so on).

"Combinatorial library" means a group of compounds obtained by parallel synthesis, designed to search for connections-hit or connection-leader, as well as to optimize the physiological activity of the compounds is hit or connection-leader, and each connection library complies with the General structural formula scaffold, and the library is a collection of related homologues or analogues.

"Connection-hit" ("Chi which means connection, shown during primary screening high desired physiological activity.

"Connection-leader" ("leader") means the connection with a significant (maximum) physiological activity, manifested by its interaction with specific biomechani.

"Parallel synthesis" means a method of doing combinatorial chemical synthesis library, which consists in simultaneously conducted in the same conditions a large number of similar reactions.

"Scaffold" means the General structural formula or molecular composition or invariant region of the compounds of the combinatorial library.

"Deputy" means a chemical moiety that is attached to scaffold or semi-synthesis in the process of their synthesis.

"Inert Deputy" ("Non-interfering substituent"means low or directionspanel radical inert to further transformations and the environment including, but not limited1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, substituted aralkyl,7-C12geterotsiklicheskikh, substituted geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, toluyl, xylenyl, biphenyl,2-C12alkoxyalkyl, 2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, substituted alkoxy, foralkyl, aryloxyalkyl, heterocyclyl, substituted heterocyclyl and nitroalkyl; where m and n have a value from 1 to 7. Preferred inert substituents are1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)n, aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.

"Substituted group, substituted radical or scaffold" means a group, the radical or scaffold, have a Deputy, including but not limited to inert Deputy, a halogen atom, a nitro-group, a cyano, alphagroup, hydroxyl group, amino group, carboxialkilnuyu group, carboxyl group, karbamoilnuyu group. For example: substituted alkyl means alkyl with one or more substituents, for example, hydroxyalkyl or methoxycarbonylethyl, amino-methoxycarbonyl-m is l, dimethylaminoethyl, 2-hydroxy-2-methoxycarbonylethyl and others; substituted amino group means an amino group which has one or two substituent, for example, acylamino group, N,N-dialkylamino group, N-acyl-N-aryl-amino group, acetyl-methoxycarbonyl-methyl-amino group, and others; substituted phenyl means phenyl, which has one or more substituents, such as 2-ethoxycarbonylphenyl, 4-amino-3-methoxy-carbonitril, 3,4-diaminophenyl and other

"Optionally substituted group optionally substituted radical or scaffold" means a group, the radical or scaffold, including groups, radicals or scaffold with deputies and without deputies. For example, the concept of optional substituted amino group includes an unsubstituted amino group and amino group containing any, not inconsistent with chemistry substituents, including, but not limited to alluminare, N,N-dialkylamino, N-acyl-N-aryl-amino, acyl-methoxycarbonylmethyl-amino group and others

"Halogen" means fluorine atom, chlorine, bromine or iodine.

"Aryl" means one or more aromatic cycles, each of which includes 5 or 6 carbon atoms. "Aryl" may be condensed political, such as naphthalene or unfused, such as biphenyl. "Substituted aryl" has one or more "not interfering" C is mustiala.

"Heterocycle" means one or more saturated, unsaturated or aromatic cycles with 5, 6 or 7 atoms, at least one of which is a heteroatom. Preferred heteroatoms are sulfur, oxygen and nitrogen. "Heterocycle" may be unfused, for example, azoles (1,3,4-thiadiazole, 1,3,4-oxadiazol), etc. or condensed politicla, for example, as bentazone (benzimidazole, benzoxazole, benzthiazole), isoleucine (Bicycle, including azole cycle, for example, oxazoline, thiazole, imidazole, etc. and Zinovy cycle, for example, pyridine, pyridazinyl, pyrimidine, pyrazinoic and others), khinazolinov, thienopyrimidine, 1,2,3,5-tetrahydro-8-thia-5,7-disallowment[a]inden-4-ones, 5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-ones, 7,8-dihydro-3H,5H-6-oxa-9-thia-1,3-diaza-fluoren-4-ones, 5,6,7,8-tetrahydro-3H-9-thia-1,3,6-triaza-fluoren-4-about, 2H-benzo[1,2,4]thiadiazine and other

"Azaheterocycle" means a heterocycle containing at least one nitrogen atom, such as piperidine, morpholine, pyrrole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, benzimidazole, benzoxazole, benzthiazole, quinoline, isoleucine (Bicycle, including azole cycle, for example, oxazoline, thiazole, imidazole, etc. and Zinovy cycle, for example, pyridine, pyridazinyl, pyrimidine, pyrazinoic and others), khinazolinov, thienopyrimidine, 1,,3,5-tetrahydro-8-thia-5,7-diaza-cyclopent[a]inden-4-ons, 5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-ones, 7,8-dihydro-3H,5H-6-oxa-9-thia-1,3-diaza-fluoren-4-ones, 5,6,7,8-tetrahydro-3H-9-thia-1,3,6-triaza-fluoren-4-about, 2H-benzo[1,2,4]thiadiazine.

"Parallel synthesis" means a method for chemical synthesis of combinatorial libraries of individual connections.

The aim of the present invention is a new substituted 2H-pyrano[2,3-C]pyridine General formula (1):

in which X represents an oxygen atom or NR3;

R1represents a group-C(O)R4, optionally substituted and optionally condensed azaheterocycle;

R2is optionally substituted hydroxyl group or optionally substituted by an amino group;

R3represents a hydrogen atom or an inert Deputy, meaning not necessarily replaced by low - or directionspanel radical inert to further transformations and the environment including, such as1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH )m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)naryloxyalkyl, heterocyclyl; where m and n have a value from 1 to 7;

R4is optionally substituted by an amino group or hydrogenated, optionally substituted azaheterocycle; provided that compounds of formula 1 are: 5-hydroxymethyl-8-methyl-2H-pyrano [2,3-C]pyridine-2-one, 3-amino-5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-one, 3-acetylamino-5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine-2-one, 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carboxylic acid, ethyl ester, 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carboxylic acid, 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carbonitrile, 5-hydroxymethyl-8-methyl-3-phenyl-2H-pyrano[2,3-C]pyridine-2-one, 5-hydroxymethyl-8-methyl-3-(4-nitrophenyl)-2H-pyrano[2,3-C]pyridine-2-one, 5-hydroxymethyl-8-methyl-3-(pyridin-2-yl)-2H-pyrano[2,3-C]pyridine-2-one, 5-hydroxymethyl-8-methyl-3-(pyridin-4-yl)-2H-pyrano[2,3-C]pyridine-2-one, 5-hydroxymethyl-8-methyl-3-(titsn-2-yl)-2H-pyrano[2,3-C]pyridine-2-one and 3-(benzothiazol-2-yl)-5-hydroxymethyl-8-revenged-2H-pyrano[2,3-C]pyridine-2-one.

The aim of the present invention is also a new combinatorial library of new substituted 2H-pyrano[2,3-C]pyridines of General formula (1) and a new focused library of new substituted 2H-pyrano[2,3-C]p is ridenow General formula (1).

The preferred option of the invention are new:

amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[3,2-C]pyridine-3-carboxylic acids of General formula 1.1:

in which R4has the above meaning;

amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[3,2-c]pyridine-3-carboxylic acids of General formula 1.2:

in which R4has the above value, a R5is inert Deputy, meaning low or directionspanel optionally substituted radical such as1-C7alkyl, C2-C7alkenyl,2-C7quinil,1-C7alkoxy, C7-C12aralkyl, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, aryl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, (CH2)m-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)naryloxyalkyl, heterocyclyl; where m and n have a value from 1 to 7;

amides of 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[3,2-C]pyridine-3-carboxylic acids of General formula 1.3:

in which R4has the above meaning;

3-azaheterocyclic-5-hydroxymethyl-methyl-pyrano[2,3-C]pyridine-2-ones of General formula 1.4:

in which R1is optionally substituted azaheterocycles radical, including: [1,3,4]thiadiazole-2-yl, [1,3,4]oxadiazol-2-yl, bendazol-2-yl, isoleucinol, azolo[4,5-b]pyridine-2-yl, azolo[4,5-C]pyridine-2-yl, azolo[4,5-C]pyridazin-6-yl, azolo[4,5-d]pyridazin-2-yl, 4-oxo-4,5-dihydrooxazolo[4,5-d]pyridazin-2-Il, azolo[4,5-b]pyrazin-2-yl, purine-8-yl, 6-oxo-6,9-dihydropyran-8-yl, hinzelin-2-yl, 4-oxo-3,4-dihydroquinazolin-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 1,2,3,5-tetrahydro-8-thia-5,7-disallowment[f]inden-4-one-2-yl, 5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyrimidine-4-one-2-yl, 5,6,7,8-tetrahydro-3H-9-thia-1,3,7-triaza-fluoren-4-one-2-yl, 5,6,7,8-tetrahydro-3H-9-thia-1,3,6-triaza-fluoren-4-one-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 1,1-dioxido-2H-benzo[1,2,4]thiadiazin-3-yl).

8-methyl-2H-pyrano[2-3-C]pyridine-5-methylacetate General formula (1.5)

in which X and R1have the above value.

8-methyl-2H-pyrano[2-3-C]pyridine-5-methylamines General formula (1.6)

in which X and R1have the above value, a R6represents an optionally substituted aminomethyl radical.

The reagents used in quality is TBE source, in most cases, are commercially available or easily obtained well-known literature methods.

Below the invention is described using specific examples of the preparation of specific compounds. The structure of the obtained compounds was confirmed by the data of chemical, chromatographic and spectral analysis. Liquid-phase parallel synthesis of new compounds and combinatorial libraries was performed using special synths "CombiSyn-012-3000" [Mbaru, Aevidence, patent of Russia 2180609, 2002; PCT WO 02/087740 A1, 2002] and equipment [Technology Platform. In Custom Chemistry; Chemical Diversity Labs, Inc.; San Diego, CA, 2002; p.5, http://www.chemdiv.com.].

The following examples illustrate but do not limit the invention.

Examples.

General information. All solvents and reagents were obtained from commercial sources, such as ACROS (Acros) (Belgium), Sigma-Aldrich (Sigma-Aldrich) (United States), Lancaster (Lancaster) (England) and Chemdiv (ChemDiv) (USA). The melting point (TPL) were obtained on the instrument company Buchi (Buchi) (Switzerland) model-520.1H and13The NMR spectra were obtained on a spectrometer firm Varian (Varian) Gemini-300 (300 MHz) in CDCl3chemical shifts are given in the scale 8 (ppm). The internal standard tetramethylsilane was.

The content of the basic substance was controlled by HPLC on the device Shimadzu (Shimadzu) 10-AV (column Luna C18, Phenomenex, 25 cm×4.6 mm, UV at 215 and 254 nm) and LC-MS instrument Applied Biosystems (Shimadzu 10-AV LC, Gilson 215 of the automatic submission of the sample, the mass spectrometer API EH, detectors UV (215 and 254 nm) and ELS, column Luna C18, Phenomenex, 5 cm×2 mm).

Analytical TLC was performed on silica gel on aluminum plates Silufol UV254(5 cm×15 cm) (Kavalier, Czech Republic) or on glass plates with 0.25 mm layer of silica gel 60 F254(Mcrck, Germany). Visualization was accomplished with UV light at a wavelength of 254 nm. For khromatograficheskoi cleaning used silica gel 5-40 μm (Chemapol, Czech Republic) and 63 μm (EM Science, USA). In accordance with these LC/MS all the synthesized compounds had a basic substance content above 95%.

Examples 1. A combinatorial library of amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-carboxylic acid 1.1{1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer downloaded 0.05 mol of the corresponding substituted amide tsianuksusnogo acid, 0.05 mol of method hydrochloride and 20 ml of absolute methanol. The reaction mass was heated to 40-45°and dropwise added to 0.1 mol (double amount) of purified piperidine. The reaction mass was kept at 40-45°and With constant stirring for 20 minutes. The amount of precipitation was filtered, washed with methanol and was led from a suitable solvent. Received combinatorial Bible the current, includes 5 compounds of General formula 1.1, including: 5-Hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C)pyridine-3-N-phenyl-carboxamide 1.1{1}: obtained with a yield of 76%, TPL 230-31°,1H (CDCl3) δ 12.58 (s, 1H), 9.41 (s, 1H), 8.61 (s, 1H), 8.23 (s, 1H), 7.64 (dd, 2H), 7.39 (t, 2H), 7.13 (dt, 1H), 5.41 (t, 1H), 4.71 (d, 2H), 2.54 (s, 3H); IR-spectrum ν (see-1): 3300, 3202, 1689, 1634. 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-N-(2-forfinal)-carboxamide 1.1{2}: obtained with a yield of 48%, TPL 254-55°,1H (CDCl3) δ 12.92 (s, 1H), 9.43 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 8.38 (dt, 1H), 7.20 (m, 3H), 5.38 (t, 1H), 4.63 (d, 2H), 2.52 (s, 3H); IR-spectrum ν (see-1): 3314, 3196, 1691, 1643. 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano [2,3-C] pyridine-3-N-(3,4-dimetilfenil)-carboxamide 1.1 {3}: obtained with a yield of 81%, TPL 232-33°,1H (CDCl3) δ 12.46 (s, 1H), 9.43 (s, 1H), 8.61 (s, 1H), 8.25 (s, 1H), 7.44 (d, 1H), 7.39 (s, 1H), 7.12 (d, 1H), 5.39 (t, 1H), 4.70 (d, 2H), 2.53 (s, 3H), 2.21 (s, 6H); IR-spectrum ν (see-1): 3428, 3185, 1677, 1630. 5-Hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-N-(3-triptoreline)-carboxamide 1.1 {4}: obtained with a yield of 60%, TPL 239°,1H (CDCl3) δ 12.84 (s, 1H), 9.45 (s, 1H), 8.61 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7.77 (d, 1H), 7.59 (t, 1H), 7.46 (d, 1H), 5.42 (t, 1H), 4.68 (d, 2H), 2.52 (s, 3H); IR-spectrum ν (see-1): 3340, 3200, 1693, 1642. 5-Hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-N-(4-methoxy-3-chlorophenyl)-carboxamide 1.1 {5}: obtained with a yield of 70%, TPL 258-60°,1H (CDCl3) δ 12.51 (s, 1H), 9.38 (s, 1H), 8.56 (s, 1H), 8.21 (s, 1H), 7.86(d, 1H), 7.46 (dd, 1H), 7.13 (d, 1H), 5.39 (t, 1H), 4.70 (d, 2H), 3.83 (s, 3H), 2.50 (s, 3H); IR-spectrum ν (see-1): 3315, 3235, 1687, 1624.

Examples 2. A combinatorial library of amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-karbouli acids 1.2 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer was loaded on a 10 ml glacial acetic acid and 0.05 mol of the corresponding primary amine. The reaction mass was heated up to 50-65°and in the warm solution was brought to 0.05 mol of the corresponding 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-carboxamide (1.1), the heating and stirring was continued for 10-15 minutes the Reaction mixture was cooled, the amount of precipitation was filtered, washed with ethanol, was led from a mixture ethanolgasoline. Received combinatorial library, including 5 compounds of General formula 1.2, including: 5-hydroxymethyl-2-(3-forfinal)imino-8-methyl-2H-pyrano[2,3-c]pyridine-3-(N-2-methylphenyl)carboxamide 1.2{1}poluce with the release of 69%, TPL 244-45°,1H (CDCl3) δ 11.91 (s, 1H), 8.80 (s, 1H), 8.31 (s, 1H), 8.24 (dd, 1H), 7.47 (m, 1H), 7.24 (m, 4H), 7.05 (m, 2H), 5.47 (t, 1H), 4.77 (d, 2H), 2.30 (s, 3H). 5-hydroxymethyl-2-phenylimino-8-methyl-2H-pyrano[2,3-C]pyridine-3-(N-3-were)carboxamid 1.2 {2} obtained with a yield of 72%, TPL 245°,1H (CDCl3) δ 12.09 (s, 1H), 8.77 (s, 1H), 8.29 (s, 1H), 7.48 (m, 6H), 7.24 (m, 2H), 6.97 (d, 1H), 5.42 (t, 1H), 4.71 (d,2H), 2.30 (s, 3H). 5-hydroxymethyl-2-(4-carbamaxepine)imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-(N-4-methoxyphenyl)carboxamide 1.2 {3} obtained with a yield of 53%, TPL 241-42°,1H (CDCl3) δ 11.70 (s, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 8.02 (d, 2H), 7.65 (d, 2H), 7.48 (d, 2H), 6.92 (d, 2H), 5.40 (t, 1H), 4.72 (d, 2H), 4.30 (q, 2H), 3.71 (s, 3H), 2.30 (s, 3H), 1.32 (t, 3H). 5-hydroxymethyl-2-(2,4-acid)imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-(N-4-methoxyphenyl)carboxamide 1.2 {4} obtained with a yield of 61%, TPL 229°,1H (CDCl3) δ 12.71 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.65 (m, 3H), 6.97 (d, 2H), 6.65 (m, 2H), 5.40 (t, 1H), 4.70 (d, 2H), 3.75 (m, 9H), 2.45 (s, 3H). 5-hydroxymethyl-2-(4-trifloromethyl)imino-8-methyl-2H-pyrano[2,3-c]pyridine-3-(N-2-forfinal)carboxamid 1.2 {5} obtained with the yield of 50%, TPL 229°,1H (CDCl3) δ 12.70 (s, 1H,), 8.81 (s, 1H), 8.31 (s, 1H), 8.45 (dt, 1H), 7.79 (d, 2H), 7.60 (d, 2H), 7.10-7.34 (m, 3H), 5.49 (t, 1H), 4.77 (d, 2H), 2.38 (s, 3H).

Examples 3. A combinatorial library of amides of 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-carboloy acid 1.3 {1-5} Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer loaded with 20 ml of ethanol and 0.01 mol of the corresponding amide 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[2,3-C]pyridine-3-carboxylic acid. The reaction mass was heated to 45-50°and dropwise with stirring was added 1 N aqueous HCl (to pH 4). The reaction mixture was cooled, the amount of precipitation was filtered, washed and water (2 30 ml), ethanol, was led from a mixture ethanolgasoline. Received combinatorial library, including 5 compounds of General formula 1.3, including: 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-(N-2-chlorophenyl)carboxamide 1.3 {7} obtained with the yield of 59%, TPL 279-80°,1H (CDCl3) δ 11.00 (s, 1H), 9.11 (s, 1H), 8.42 (s, 1H), 8.40 (d, 1H), 7.56 (dd, 1H), 7.40 (dt, 1H), 7.20 (dt, 1H), 5.45 (t, 1H), 4.80 (d, 2H), 2.62 (s, 3H); IR-spectrum ν 3201, 1731, 1670, 1594, 1545, 1442, 1415, 1215, 1015. 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-(N-4-chlorophenyl)carboxamide 1.3 {2} obtained with a yield of 54%, TPL 269-70°,1H (CDCl3) δ 10.65 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 7.70 (d, 2H), 7.42 (dd, 2H), 5.54 (t, 1H), 4.80 (d, 2H), 2.56 (s, 3H); IR-spectrum ν 3235, 1727, 1664, 1598, 1551, 1490, 1402, 1215, 1149, 1008. 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-(N-4-carbamaxepine)carboxamid 1.3 {3} obtained with a yield of 49%, TPL 277°,1H (CDCl3) δ 10.79 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 7.96 (d, 2H), 7.85 (d, 2H), 5.50 (t, 1H), 4.83 (d, 2H), 3.83 (s, 3H), 2.60 (s, 3H); IR-spectrum ν 3196, 1728, 1671, 1600, 1550, 1408, 1291, 1215, 1015. 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-(N-3-were)carboxamid 1.3 {4} obtained with a yield of 61%, TPL 256-57°,1H (CDCl3) δ 10.50 (s, 1H), 8.86 (s, 1H), 8.38 (s, 1H), 7.51 (m, 2H), 7.24 (t, 1H), 6.97 (d, 1H), 5.53 (t, 1H), 4.71 (d, 2H), 2.60 (s, 3H), 2.30 (s, 3H); IR-spectrum ν 3308, 1700, 1639, 1610, 1492, 1397, 1263, 1178. 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[2,3-C]pyridine-3-(N-3-triptoreline)carboxamid 1.3 {5} obtained with the yield 56%, TPL 261° C,1H (CDCl3) δ 10.75 (s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.88 (d, 1H), 7.62 (t, 1H), 7.56 (dd, 1H), 5.50 (t, 1H), 4.80 (d, 2H), 2.62 (s, 3H); IR Spectr ν 3484, 3245, 1722, 1656, 1597, 1563, 1451, 1327.

Examples 4. A combinatorial library of 3-(5-amino-[1,3,4}thiadiazole-2-yl)-5-hydroxymethyl-8-methyl-pyrano[2,3-C]pyridine-2-ones 1.4 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer downloaded 0.05 mol of the corresponding substituted 2-cyanomethyl-[1,3,4]thiadiazole, 0.05 mole method hydrochloride and 20 ml of absolute methanol. The reaction mass was heated to 40-45°and dropwise added to 0.05 mol of purified piperidine. The reaction mass was heated with constant stirring for 40 minutes. The amount of precipitation was filtered, washed with methanol and was led from a suitable solvent. Received combinatorial library, including 5 compounds of General formula 1.4, including: 5-hydroxymethyl-8-methyl-3-[5-(3-chloro-4-forgenerating)-[1,3,4]thiadiazole-2-yl)-2H-pyrano[2,3-C]pyridine-2-it 1.4 {1} obtained with the yield 40%, TPL 336-338°,1H (CDCl3) δ 10.60 (s, 1H), 9.00 (s, 1H), 8.35 (s, 1H), 8.05 (dd, 1H), 7.28-7.53 (m, 2H), 5.48 (t, 1H), 4.80 (d, 2H), 2.59 (s, 3H); LC-MS m/z 418 (M+), 417, 400, 227, 191, 145, 130. 5-Hydroxymethyl-8-methyl-3-[5-(2-chlorpheniramine)-[1,3,4]thiadiazole-2-yl)-2H-pyrano[2,3-C]pyridine-2-it 1.4 {2} obtained with a yield of 57%, TPL 335-337°,1H (CDCl3) δ 9.92 (s, 1H), 9.03 (s, 1H), 8.37 (s, 1H), 8.18 (d, 1H), 7.50 (dd, 1H), 7.39 (dt, 1H), 7.14 (dt, 1H), 5.47 (t, 1H), 4.80 (d, 2H), 2.60 (s, 3H); LC-MS m/z 400 (M+), 365, 191, 125, 111. 5-Hydroxymethyl-8-methyl-3-[5-(3-methylphenylimino)-[1,3,4]thiadiazole-2-yl)-2H-pyrano[2,3-C]pyridine-2-it 1.4 {3} obtained with a yield of 60%, TPL 314-316°,1H (CDCl3) δ 9.66 (s, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 7.43 (m, 2H), 7.24 (t, 1H), 6.85 (d, 1H), 5.48 (t, 1H), 4.85 (d, 2H), 2.60 (s, 3H), 2.30 (s, 3H); LC-MS m/z 380 (M+), 379, 363, 348, 190, 105.

5-Hydroxymethyl-8-methyl-3-[5-(tetrahydrofuran-2-methylamino)-[1,3,4]thiadiazole-2-yl)-2H-pyrano[2,3-C] - perigee-2-it 1.4 {4} obtained with a yield of 76%, TPL 276-278°,1H (CDCl3) δ 8.88 (s, 1H), 8.35 (s, 1H), 8.05 (t, 1H), 5.45 (t, 1H), 4.90 (d, 2H), 4.07 (m, 1H), 3.88 (m, 1H), 3.60 (m, 1H), 3.43 (m, 2H), 2.60 (s, 3H), 1.55-2.05 (m, 4H); LC-MS m/z 374 (M+), 304, 290, 274, 185, 101, 85. 5-hydroxymethyl-8-methyl-3-[5-(furyl-2-methylamino)-[1,3,4]thiadiazole-2-yl)-2H-pyrano [2,3-C] pyridine-2-it 1.4 {5} obtained with the yield of 71%, TPL 274-276°,1H (CDCl3) δ 8.91 (s, 1H), 8.38 (s, 1H), 8.40 (t, 1H), 7.60 (s, 1H), 6.40 (m, 2H), 5.49 (t, 1H), 4.81 (d, 2H), 4.58 (d, 2H), 2.61 (s, 3H).

Examples 5. Combinatorial library (8-methyl-2H-pyrano[2,3-C]pyridine-5-yl)methyl acetates 1.5 {1-5}. Parallel synthesis of combinatorial libraries was performed in the synthesizer "CombiSyn-012-3000". In each of the 5 reactors synthesizer downloaded 0.025 mol of acetic anhydride and 0.01 mol of the corresponding 5-hydroxymethyl-8-methyl-2H-pyrano[2,3-C]pyridine. The reaction mass was heated and under stirring and boil for 60 minutes Obtained with whom thou cooled, the amount of precipitation was filtered, washed on the filter with water (3 x 50 ml), ethanol (2 25 ml) and was led from ethanol. Received combinatorial library, including 5 compounds of General formula 1.13, including: [2-(4-carbamaxepine)imino-8-methyl-3-N-(2-were)carboxamido-2H-pyrano[2,3-C]pyridine-5-yl]acetate 1.5 {1} obtained with the yield 79%, TPL 202-203°,1H (CDCl3) δ 11.79 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.21 (d, 1H), 8.03 (d, 2H), 7.46 (d, 2H), 7.23 (t, 2H), 7.07 (dt, 2H), 5.40 (s, 2H), 4.32 (q, 2H), 2.29 (s, 6H), 2.00 (s, 3H), 1.31 (t, 3H). [2-(4-triptoreline)imino-8-methyl-3-N-(4-were)carboxamido-2H-pyrano[2,3-C]pyridine-5-yl]acetate 1.5 {2} obtained with the yield 68%, TPL 212-214°,1H (CDCl3) δ 11.69 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 7.78 (d, 2H), 7.57 (dd, 4H), 7.16 (d, 2H), 5.39 (s, 2H), 2.30 (s, 3H), 2.22 (s, 3H). [2-(2,4-acid)imino-8-methyl-3-N-(2-forfinal)carboxamido-2H-pyrano[2,3-c]pyridine-5-yl]acetate 1.5 {3} obtained with the yield 81%, TPL 183-184°,1H (CDCl3) δ 12.80 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.21 (m, 1H), 7.42 (d, 1H), 7.18-7.29 (m, 3H), 6.72 (d, 1H), 6.58 (dd, 1H), 5.39 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H), 2.39 (s, 3H), 2.01 (s, 3H). [2-(2,4-acid)imino-8-methyl-3-N-(2-ethylphenyl)carboxamido-2H-pyrano[2,3-C]pyridine-5-yl]acetate 1.5 {4} obtained with the yield 67%, TPL 182°,1H (CDCl3) δ 12.40 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 8.05 (d, 1H), 7.35 (d, 1H), 7.10-7.25 (m, 3H), 6.68 (d, 1H), 6.60 (dd, 1H), 5.40 (s, 2H), 3.81 (s, 3H), 3.71 (s, 3H), 2.70 (q, 2H), 2.32 (s, 3H), 2.03 (s, 3H), 1.04 (t, 3H). [2-(4-(6-methyl-benzothiazolyl-2)phenyl)imino-8-methyl-3-N-2-ethylphenyl)carboxamido-2H-pyrano[2,3-C]pyridine-5-yl]acetate 1.5 {5} obtained with the yield of 70%, TPL 191-193°,1H (CDCl3) δ 11.90 (s, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 8.22 (d, 1H), 8.13 (d, 2H), 7.89 (d, 2H), 7.51 (d, 2H), 7.33 (d, 1H), 7.23 (t, 2H), 7.10 (t, 1H), 5.40 (t, 1H), 2.70 (q, 2H), 2.44 (s, 3H), 2.30 (s, 3H), 2.05 (s, 3H), 1.11 (t, 3H).

Example 6. Focused library, including new 2H-pyrano[2,3-C]pyridines of General formula (1) was tested for the ability to inhibit the activity of protein kinases, which were determined as follows. The solution of the polypeptide (Calbiochem, USA), consisting of a random sequence of glutamic acid and tyrosine in the proportion 4:1, respectively, was maintained in the wells of 96 well plates with optically transparent bottom during the night. During this time, the polypeptide firmly sorbirovtsa on the surface of the hole. Adsorbed polypeptide served as substrate for the kinase, which was fosfaurilirovania tyrosine in this polypeptide.

100 microlitres 1U kinase (Calbiochem, USA, 1U is defined as the concentration of this enzyme is able to attach to the substrate 1 picomole phosphate for 1 minute) was added to the wells with the adsorbed polypeptide without the test compounds (control activity) or in the presence of different concentrations of these compounds. After a 30 minute incubation the solutions were removed by shaking from the wells and the wells were washed twice with saline. The wells were filled with 100 microlitres solution anti-phosphotyrosine monoclonal what IGg antibodies conjugated with horseradish peroxidase from horseradish (Sigma, USA). The amount of bound peroxidase antibodies was determined by the activity of peroxidase, which, in turn, was determined by conversion speed peroxidase substrate (OPD, o-phenolenediamine dihydrochloride, Sigma) into a colored product. The concentration of the product formed in 30 minutes the reaction was determined by optical density at 490 nm, measured using a parallel 96-well reader VICTOR2V (PerkinElmer, USA).

To calculate the percentage inhibition of kinase activity each 96-well plate contained the following control wells: 1) the reaction solution containing all components except kinase and 2) the reaction solution together with the kinase. The optical density measured in control wells (1), was taken as zero activity (OD0), and the optical density measured in control wells (2), 100% (OD100). The optical density measured in the presence of test compounds (ODi), was expressed as a percentage of the maximum activity. The percentage inhibition of kinase activity was calculated by the following formula:

Table 2 shows the values of inhibition of ABL kinase of some of the tested new 2H-pyrano[2,3-C]pyridines of General formula (1), confirming their biological.

Table 2.

Inhibition of ABL kinases new 2H-pyrano[2,3-C]pyridine General formula (1).
No. p.pConnection typeStructure% inhibition 10 μM
11.133,1
21.342,5
31.463,9

1. Substituted 2H-pyrano[2,3-C]pyridine General formula (1)

in which X represents an oxygen atom or a group NR3;

R1represents a group-C(O)R4, optionally substituted and optionally condensed azaheterocycle;

R2is optionally substituted hydroxyl group or optionally substituted by an amino group;

R3represents a hydrogen atom or an inert Deputy denoting optionally substituted low - or directionspanel radical, including such as1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3 -C10cycloalkenyl, phenyl, aryl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, -(CH2)-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)naryloxyalkyl, heterocyclyl, where m and n have a value from 1 to 7;

R4is optionally substituted by an amino group or hydrogenated, optionally substituted azaheterocycle;

provided that the compounds of formula 1 are:

5-hydroxymethyl-8-methyl-2H-pyrano[3,2-C]pyridine-2-one,

3-amino-5-hydroxymethyl-8-methyl-2H-pyrano[3,2-C]pyridine-2-one,

3-acetylamino-5-hydroxymethyl-8-methyl-2H-pyrano[3,2-C]pyridine-2-one,

5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[3,2-C]pyridine-3-carboxylic acid,

ethyl ester of 5-hydroxymethyl-8-methyl-2H-pyrano[3,2-C]pyridine - carboxylic acid,

5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[3,2-C]pyridine-3-carbonitrile ,

5-hydroxymethyl-8-methyl-3-phenyl-2H-pyrano[3,2-C]pyridine-2-one,

5-hydroxymethyl-8-methyl-3-(4-nitrophenyl)-2H-pyrano[3,2-C]pyridine-2-one,

5-hydroxymethyl-8-methyl-3-(pyridin-2-yl)-2H-pyrano[3,2-C]pyridine-2-one,

5-hydroxymethyl-8-methyl-3-(pyridin-4-yl)-2H-pyrano[3,2-C]pyridine-2-one,

5-hydroxymethyl-8-methyl-3-(thiophene-2-yl)-2H-pyrano[3,2-C]pyridine-2-one,

3-(best the azole-2-yl)-5-hydroxymethyl-8-methyl-2H-pyrano[3,2-C]pyridine-2-one.

2. Compounds according to claim 1, represents amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[3,2-C]pyridine-3-carboxylic acids of General formula 1.1:

in which R4has the above value.

3. Compounds according to claim 1, represents amides of 5-hydroxymethyl-2-imino-8-methyl-2H-pyrano[3,2-C]pyridine-3-carboxylic acids of General formula 1.2:

in which R4has the above meaning;

R10is inert Deputy, meaning not necessarily replaced by low - or directionspanel radical, including such as1-C7alkyl, C2-C7alkenyl,2-C7quinil, C1-C7alkoxy, C7-C12aralkyl, geterotsiklicheskikh,7-C12alkaryl,3-C10cycloalkyl,3-C10cycloalkenyl, phenyl, substituted phenyl, aryl, C2-C12alkoxyalkyl,2-C10alkylsulfonyl,2-C10alkylsulfonyl, -(CH2)-O-(C1-C7alkyl), -(CH2)m-N(C1-C7alkyl)naryloxyalkyl, heterocyclyl, where m and n have a value from 1 to 7.

4. Compounds according to claim 1 representing amides of 5-hydroxymethyl-8-methyl-2-oxo-2H-pyrano[3,2-C]pyridine-3-carboxylic acids of General formula 1.3

in which R4has the above value.

5. Compounds according to claim 1, represents a 3-azaheterocyclic-5-hydroxymethyl-8-methylpurine[2,3-C]pyridine-2-ones of General formula 1.4

in which R1is optionally substituted azaheterocyclic moiety selected from the group: [1,3,4]thiadiazole-2-yl, [1,3,4]oxadiazol-2-yl, bendazol-2-yl, isoleucinol, azolo[4,5 - b]pyridine-2-yl, azolo[4,5-C]pyridine-2-yl, azolo[4,5-C]pyridazin-6-yl, azolo[4,5-d]pyridazin-2-yl, 4-oxo-4,5-dihydrooxazolo[4,5-d]pyridazin-2-Il, azolo[4,5-b]pyrazin-2-yl, purine-8-yl, 6-oxo-6,9-dihydropyran-8-yl, hinzelin-2-yl, 4-oxo-3,4-dihydroquinazolin-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl,1,2,3,5-tetrahydro-8-thia-5,7-disallowment[f]inden-4-one-2-yl, 5,6,7,8-tetrahydro-ZN-benzo[4,5]thieno[2,3-d]pyrimidine-4-one-2-yl, 5,6,7,8-tetrahydro-ZN-9-thia-1,3,7-triaza-fluoren-4-one-2-yl, 5,6,7,8-tetrahydro-ZN-9-thia-1,3,6-diazafluoren-4-one-2-yl, 4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-yl, 1,1-dioxido-2H-benzo[1,2,4]thiadiazin-3-yl.

6. Compounds according to claim 1, which represents 8-methyl-2H-pyrano[2-3-C]pyridine-5-methylacetate General formula (1.5)

in which X and R1have the above values.

7. Compounds according to claim 1, which represents 8-methyl-2H-pyrano[2-3-C]pyridine-5-methylamines General formula (1.6)

in which X and R1have the above values, R6represents optionally substituted by an amino group.

8. A combinatorial library of compounds to search for physiologically active compounds hits or compounds leaders, consisting of substituted 2H-pyrano[2,3-C]pyridines of General formula (1) according to any one of claims 1 to 7.

9. Focused library to search for physiologically active compounds leaders, including its composition, at least one of the substituted 2H-pyrano[2,3-C]pyridines of General formula (1) according to any one of claims 1 to 7.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention proposes applying derivatives of benzopyranoimidazole and benzothiopyranoimidazole as inhibitors of activity of phosphodiesterase VII, new derivatives of benzopyranoimidazole of the general formula (I)

with radical values given in the invention claim that elicit the above said activity and a pharmaceutical preparation based on thereof. Claimed derivatives elicit specific inhibition of rolipram-insensitive cAMP-phosphodiesterase (phosphodiesterase VII) in combination with good tolerance that allows their applying in asthma treatment. Indicated compounds show activity with respect to inhibition of tumor necrosis factor (TNF) producing that allows their applying for treatment of some autoimmune diseases.

EFFECT: valuable medicinal and biochemical properties of compounds.

3 cl, 2 tbl, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

The invention relates to a new 1.8-fused derivative of 2-Hinayana formula (I), where A, X, R1, R2, R3, R4, R5, R6such as defined in the claims

The invention relates to derivatives of 1-arylsulfonyl, arylcarbamoyl or aristoteleion General formula I where L is selected from the group consisting of Co, CS and SO2; R1and R2independently selected from the group consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6), provided that when L - SO2, R1and R2at the same time do not represent hydrogen; R3independently represents 1 to 3 groups consisting of hydrogen, halogen, alkyl (C1-C6), haloalkyl (C1-C6); X is chosen from (CH2)nor Y(CH2)n-1where Y Is O or S, and n = 1, 2, 3

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed in the 3,4-, 6,7 - and 7,8-positions coumarin system, the General formula I

< / BR>
where R1R2= NHCH=C(CO2R6)CO., R3= NO2or NH2, R4= R5= H, R6= H or C2H5; R1R2= NHCH=C(CO2R6)CO., R3= R4= H, R5= F, R6= H or C2H5; R1R2= CO(CO2R6) = СНNH, R3= R4= R5= H, R6= H or C2H5; R1R2= R3R4= NHCH= C(CO2R6)CO., R5= H, R6= H or C2H5; R1= H or HE, R2= R5= N, R3R4= -NHCH=C(CO2R6)CO., R6= H or C2H5; R1= HE, R2= R3= N, R4R5= -CO(CO2R6) = СНNH, R6= H or C2H5; R1= R5= N, R2- CH3or CF3, R3R4= CO(CO2R6)C = CHNH, R6= H or C2H5and their pharmaceutically acceptable salts

The invention relates to new substituted dihydropyrimidines, methods for their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, in particular migraine

The invention relates to tricyclic derivatives of pyrrole General formula (I), where R1-R4denote hydrogen, halogen, lower alkyl, phenyl, cycloalkyl or lower alkoxy, a R2indicates additional lower alkoxycarbonyl, acyloxy or mesilate; R5denotes lower alkyl; R6, R7represent hydrogen or lower alkyl; X represents-CH2CH(C6H5), -CH= C(C6H5)-, -YCH2-, -CH=CH - (CR11R12)n; R11and R12denote hydrogen, phenyl, lower alkyl; h denotes 1-3 and Y denotes O or S, and pharmaceutically acceptable acid additive salts

The invention relates to a new diisobutylaluminum connection, which has an excellent activity, which increases potassium exchange by opening potassium channels and therapeutic agents for the treatment of hypertension, angina pectoris and asthma, which contain diazabicyclo connection as the active agent

The invention relates to pharmaceutical compounds, their preparation and use

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, transplantology.

SUBSTANCE: method involves applying (R)-ibuprofen methanesulfonamide and its nontoxic salts for preparing medicinal agents used for prophylaxis or treatment of ischemic, reprefusion and functional damages of transplanted organs. Invention provides prophylaxis such complications as delayed function of transplant arising in transplantation of organs.

EFFECT: valuable medicinal properties of medicinal agent.

5 cl, 5 tbl, 1 dwg, 2 ex

FIELD: medicine, infectious diseases.

SUBSTANCE: invention relates to a method for preparing capsule antigen of meliodosis pathogen eliciting anti-phagocytic activity. Method involves culturing the strain B. pseudomallei, inactivation, isolation of glycoprotein by gel-filtration and ion-exchange chromatography methods resulting to preparing glycoprotein with molecular mass 200 kDA consisting of 90% of carbohydrates, 10% of proteins and comprising 2.17% of nitrogen, 46.4% of carbon and 8.09% of hydrogen. Advantage of method involves preparing the purified glycoprotein eliciting anti-phagocytic activity.

EFFECT: improved method for preparing, valuable properties of antigen.

2 dwg, 5 ex

FIELD: medicine, therapy.

SUBSTANCE: invention relates to treatment of vasculitis and erythematosus lupus. Method involves administration of 15-deoxyspergualine or its analogous by two or more courses with break for 4 days to 5 weeks. Period between successive injections of preparation within the treatment course is up to 48 h and the treatment course is at least 5-7 days. Method provides high treatment effect and reducing the total dose of 15-deoxyspergualine or its analogous.

EFFECT: enhanced effectiveness of treatment.

25 cl, 2 dwg, 3 ex

Immunosupressor // 2253448

FIELD: drugs, medicine.

SUBSTANCE: invention relates to application of 1-methylindolyl-3-thioacetic acid tris-(2-hydroxyethyl)ammonia salt, which is known hypolipidemic agent, as immunosuppressor. Present invention ales it possible to produce pharmaceuticals for transplanted organ and tissue rejection prophylaxis or treatment of various immune-associated diseases.

EFFECT: new drug for transplant rejection prophylaxis or treatment of immune-associated diseases.

3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with cyclosporin-containing and practically oil-free compositions being of immunosuppressive action. The composition contains a hydrophilic surface-active substance, a lipophilic component, a lipophilic surface-active substance and ethanol. As a hydrophilic surface-active substance this composition contains ether of fatty acid and polyoxyethylene sorbitane and product of either natural or hydrogenised castor oil and ethylenoxide; as a lipophilic component and lipophilic surface-active substance it contains ether of fatty acid and sorbitane. The suggested composition has been designed as a gelatinous capsule with solid covering. The present innovation solves the problem dealing with stability of galena compositions with cyclosporin: at treating with water the composition develops practically stable microemulsion.

EFFECT: higher efficiency of application.

11 cl, 2 ex

FIELD: antibiotics, pharmacy.

SUBSTANCE: invention relates to stabilization of rapamycin or rapamycin derivative with immunosuppressive properties and sensitive to oxidation. Method for stabilization involves addition of antioxidant to the purified rapamycin in small concentrations - below 1% as recalculated for rapamycin mass. Also, invention relates to a solid mixture containing rapamycin and antioxidant taken in the catalytic amount. Antioxidant represent preferably 2,6-di-tert.-butyl-4-methylphenol. The stabilized rapamycin shows high stability against oxidation, it can be stored as formulation without package before it's the following treatment and can be used in an unmodified form for preparing the required galenic composition.

EFFECT: improved stabilizing method.

14 cl, 3 dwg, 2 ex

The invention relates to medicine, specifically to pharmacology

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

The invention relates to the field of medicine and relates to a composition in the form of pre-prepared emulsion or microemulsion concentrate, intended for oral administration and comprising a cyclosporin or macrolide and media, as well as a soft or hard gelatin capsules containing the specified composition, and method of reducing the variability of the bioavailability of cyclosporine or macrolide using the composition

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new substituted 7-sulfonyl-benzo[b][1,4]diazepines of the general formula (1) , their pharmaceutically acceptable salts, N-oxides or hydrates that elicit properties of a protein kinase inhibitor that can be used in pharmaceutical industry. In compounds of the general formula (1) R1 and R2 represent independently of one another hydrogen atom, inert substitute, optionally substituted carboxymethyl group, optionally substituted carbamoylmethyl group; R3 and R4 represent independently of one another hydrogen atom or inert substituted, or R3 and R4 in common with carbon atom to which they are bound form optionally substituted (C3-C7)-cycloalkyl, optionally substituted (C4-C7)-heterocyclyl or optionally substituted ethylene group; R5 represents optionally substituted amino-group or optionally substituted azaheterocyclyl. Also, invention relates to sulfochlorides of the general formula (2) that are used for preparing compound of the formula (1), and to methods for preparing compounds of general formulae (1) and (2). Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injection formulations placed into pharmaceutically acceptable package, and to the focused library for the search of biologically active compound-leaders.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds.

7 cl, 2 sch, 1 tbl, 3 ex

Up!